Kinetics of gentamicin in plasma of nonpregnant, pregnant, and fetal guinea pigs and its distribution in fetal tissues

Abstract

Nonpregnant and pregnant guinea pigs in the last third of gestation were injected intramuscularly with 4 mg of gentamicin per kg, and drug concentrations in plasma were determined by radioimmunoassay at several intervals after injection. The maximum gentamicin concentration was significantly lower in pregnant than in nonpregnant animals (14.6 ± 0.7 ,ug/ml versus 21.6 ± 0.7 ,ug/ml), and the peak time occurred significantly later (0.57 ± 0.12 h versus 0.13 ± 0.02 h). Four hours after gentamicin injection, drug concentrations in plasma were 2.1 ± 0.8 and 0.3 ± 0,1 ,ug/ml in pregnant and nonpregnant animals, respectively. Pregnant animals therefore eliminated the drug from their plasma more slowly. These data provide good evidence that the kinetics of plasma gentamicin varies in pregnant females because its volume of distribution was larger in pregnant than in nonpregnant animals. Detectable but small amounts of gentamicin (c 0.50 ,zg/ml) were found in the plasma of 46 of 57 fetuses. However, no net variations in these concentrations were observed during the period between 15 min and 6 h after injection to the mother. Gentamicin concentrations were also determined in the kidneys, liver, lungs, heart, and brain of fetal guinea pigs after administration to their mothers of one daily injection of 4 mg/kg for 7 days. Gentamicin was present in all these fetal organs; however, as in the adult organs, the kidneys contained far more than any of the others. Gentamicin concentrations were not significantly different in the kidney cortex and medulla (1.79 ± 0.16 versus 1.48 + 0.92 ,Lg/g), indicating that, contrary to what is observed for adults, renal accumulation of gentamicin in the fetus does not occur preferentially in the cortex.

Long-Term Effects of Mild Oligonephronia Induced In Utero by Gentamicin in the Rat

“…In the urine of 3-mo-old animals in the gentamicin group, RIA of gentamicin was performed as previously described (22).…”

Effect of fetal exposure to gentamicin on kidneys of young guinea pigs

“…In view of the developmental pattern of proximal tubule length in this species (12), it is clear that any effect of gentamicin on tubular growth would be more easily detectable in the late stages of development, when the growth rate is fast, than in the early stages, when it is slower. The more pronounced impairment of the juxtamedullary than of the superficial nephrons observed here was probably a result of the centrifugal pattern of renal cortex maturation which, as already suggested, might for a while preserve the superficial nephrons from the delivery, accumulation, and, hence, toxicity of gentamicin (4,9). In addition, as previously demonstrated in fetal guinea pigs (12), the maturation of the superficial nephrons is accompanied by a morphologic imbalance between glomerular and tubular growth and also by a phase of functional glomerular preponderance which may exist for the handling of gentamicin as for other substances.…”

“…The amount of gentamicin found in the renal cortex of 3-day-old neonates more than 2 weeks after treatment of the mother had ceased was four times larger than the amount previously found in the renal cortex of 55-day-old fetuses on the' day after their mother had been given the last injection of a similar series (9). This indicates that the drug, which was probably released from all the maternal and fetal tissues, continued to accumulate in the developing kidney, the more so as the renal blood flow and glomerular filtration rate increased with age (10,11).…”

“…Consequently, in the neonate kidney, as in that of the adult (7,8), a much larger amount of gentamicin was found in the cortex than in the medulla, whereas in the fetus, the same amount was present in both tissues (9). This developmental pattern of intrarenal gentamicin distribution probably resulted from the changes in intrarenal blood flow distribution which normally take place in the developing kidney.…”

“…It was previously shown that when gentamicin is administered to pregnant guinea pigs, it accumulates in the fetal kidney, which, as in the adult, was found to be the major site of gentamicin deposition (9). Gentamicin is known to be nephrotoxic.…”